title: Specific mtDNA mutations in mouse carcinoma cells suppress their tumor formation via activation of the host innate immune system.
abstract: In mammalian species, mitochondrial DNA (mtDNA) with pathogenic mutations that induce mitochondrial respiration defects has been proposed to be involved in tumor phenotypes via induction of enhanced glycolysis under normoxic conditions (the Warburg effects). However, because both nuclear DNA and mtDNA control mitochondrial respiratory function, it is difficult to exclude the possible contribution of nuclear DNA mutations to mitochondrial respiration defects and the resultant expression of tumor phenotypes. Therefore, it is important to generate transmitochondrial cybrids sharing the same nuclear DNA background but carrying mtDNA with and without the mutations by using intercellular mtDNA transfer technology. Our previous studies isolated transmitochondrial cybrids and showed that specific mtDNA mutations enhanced tumor progression as a consequence of overproduction of reactive oxygen species (ROS). This study assessed whether mtDNA mutations inducing ROS overproduction always enhance tumor progression. We introduced mtDNA from senescence-accelerated mice P1 (SAMP1) into C57BL/6J (B6) mice-derived Lewis lung carcinoma P29 cells, and isolated new transmitochondrial cybrids (P29mtSAMP1 cybrids) that overproduced ROS. The inoculation of the cybrids into B6 mice unexpectedly showed that mtDNA from SAMP1 mice conversely induced tumor suppression. Moreover, the tumor suppression of P29mtSAMP1 cybrids in B6 mice occurred as a consequence of innate immune responses of the host B6 mice. Enzyme pretreatment experiments of P29mtSAMP1 cybrids revealed that some peptides encoded by mtDNA and expressed on the cell surface of P29mtSAMP1 cybrids induce increased IL-6 production from innate immune cells (dendritic cells) of B6 mice, and mediate augmented inflammatory responses around the tumor-inoculated environment. These observations indicate presence of a novel role of mtDNA in tumor phenotype, and provide new insights into the fields of mitochondrial tumor biology and tumor immunology.
authors.affiliation: Faculty of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan ; Japan Society for the Promotion of Science, Tokyo, Japan ; Department of Molecular Immunology and Inflammation, National Center for Global Health and Medicine, Tokyo, Japan.
authors.forename: Hirotake
authors.initials: H
authors.lastname: Imanishi
authors.forename: Gaku
authors.initials: G
authors.lastname: Takibuchi
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Kaori
authors.initials: K
authors.lastname: Ishikawa
authors.forename: Kazuto
authors.initials: K
authors.lastname: Nakada
authors.forename: Masayuki
authors.initials: M
authors.lastname: Mori
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kikkawa
authors.forename: Keizo
authors.initials: K
authors.lastname: Takenaga
authors.forename: Noriko
authors.initials: N
authors.lastname: Toyama-Sorimachi
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Hayashi
mesh_terms: D000818:Animals; D002277:Carcinoma / Q000235:genetics* / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000235:genetics*; D003713:Dendritic Cells / Q000276:immunology; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D018014:Gene Transfer Techniques; D005838:Genotype; D006822:Hybrid Cells / Q000276:immunology* / Q000637:transplantation; D007113:Immunity, Innate / Q000235:genetics*; D015850:Interleukin-6 / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D016207:Cytokines; D004272:DNA, Mitochondrial; D015850:Interleukin-6; D017382:Reactive Oxygen Species